High resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types

  1. Landry Blanc
  2. Isaac B Daudelin
  3. Brendan K Podell
  4. Pei-Yu Chen
  5. Matthew Zimmerman
  6. Amanda J Martinot
  7. Rada M Savic
  8. Brendan Prideaux
  9. Veronique Anne Dartois  Is a corresponding author
  1. Rutgers, The State University of New Jersey, United States
  2. Colorado State University, United States
  3. Harvard Medical School, United States
  4. University of California, San Francisco, United States

Abstract

Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 3, 4 and 5. Model codes are provided for the base model and full model.

Article and author information

Author details

  1. Landry Blanc

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Isaac B Daudelin

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Brendan K Podell

    Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Pei-Yu Chen

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Matthew Zimmerman

    Public Health Research Institute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Amanda J Martinot

    Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rada M Savic

    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Brendan Prideaux

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Veronique Anne Dartois

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    For correspondence
    veronique.dartois@rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9470-5009

Funding

National Institutes of Health (U01-HL131072)

  • Veronique Anne Dartois

National Institutes of Health (R01-AI111967)

  • Veronique Anne Dartois

Bill and Melinda Gates Foundation (OPP1174780)

  • Veronique Anne Dartois

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were performed in Biosafety Level 3 facilities and approved by the Institutional Animal Care and Use Committee (IACUC protocol number 16016) of the New Jersey Medical School, Rutgers University, Newark, NJ, under the guidelines and regulations of the National Institutes of Health.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Received: August 15, 2018
  2. Accepted: November 13, 2018
  3. Accepted Manuscript published: November 14, 2018 (version 1)
  4. Version of Record published: November 21, 2018 (version 2)

Copyright

© 2018, Blanc et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Landry Blanc
  2. Isaac B Daudelin
  3. Brendan K Podell
  4. Pei-Yu Chen
  5. Matthew Zimmerman
  6. Amanda J Martinot
  7. Rada M Savic
  8. Brendan Prideaux
  9. Veronique Anne Dartois
(2018)
High resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types
eLife 7:e41115.
https://doi.org/10.7554/eLife.41115

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